A bench to bedside approach is used in our studies of human genetic disorders, integrating both basic and clinical research. We focus on a rare genetic disorder, Gaucher disease, and a common complex disorder, Parkinson disease. Most inherited diseases are characterized by a wide range of patient presentations, yet the factors contributing to this heterogeneity are elusive. Gaucher disease, the most common of the sphingolipidoses, is studied as a prototype because of the broad spectrum of clinical diversity resulting from this recessively inherited enzyme deficiency. Gaucher disease affects approximately 10,000 to 20,000 Americans and is more common among Ashkenazi Jews. Natural history studies, as well as molecular and biochemical evaluations in humans and animals, are used to enhance our understanding of heterogeneity in Gaucher disease and our ability to develop rational therapy for patients. In contrast, Parkinson disease is a common disorder that affects over 1.5 million Americans. The techniques, insights, and experience gained from our studies of Gaucher disease can then be applied to other Mendelian disorders and ultimately to the challenges of complex illnesses like Parkinson disease. An important consequence of our research has been the discovery of an association between Gaucher disease and parkinsonism. Our clinical studies of patients with both disorders, neuropathologic evaluations, family studies and screening of tissues and DNA samples from subjects with Parkinson disease have all supported this link. Evaluations of patients with Gaucher disease and Parkinson disease demonstrate both classic and atypical features. Many different genotypes are encountered. Currently, prospective clinical studies of these subjects and their affected or at-risk relatives using Positron Emission Tomography studies of the brain as well as other diagnostic modalities are in progress. Neuropathology from several of these cases demonstrated large, immunoreactive Lewy bodies in the substantia nigra and cortex. Furthermore, family histories of families of patients with Gaucher disease identified several carrier relatives who developed parkinsonism. This prompted an examination of the glucocerebrosidase gene (GBA) in large cohorts with Parkinson disease. Complete gene sequencing of GBA was initially performed in brain samples from individuals who died carrying the clinical and/or pathologic diagnosis of Parkinson disease and demonstrated that a significant number had mutations in GBA. These studies indicate that an alteration in glucocerebrosidase, even in heterozygotes, contribute to a vulnerability to synecleinopathies. This finding has been replicated in other large Parkinson cohorts, suggesting that mutations in glucocerebrosidase are a frequent inherited risk factor associated with parkinsonism. We coordinated and completed a large multi-center collaborative study including subjects seen at 16 centers around the world. This study of over 5000 patients with Parkinson disease and an equal number of controls demonstrates that the odds ratio for carrying a GBA mutation is greater than 5, rendering glucocerebrosidase among the most common risk factors for parkinsonism known to date. Many of the same centers then collaborated to determine the frequency of glucocerebrosidase mutations in Lewy body dementia, which has an odds ratio of over 8, even higher than in Parkinson disease. Under a new clinical imaging protocol, we performed over 100 PET studies on patients with and without Parkinson symptoms, and demonstrated that GBA-associated Parkinson disease has blood flow patterns seen in Lewy body dementias, while fluoro-dopa uptake is similar to classic Parkinson disease.We are also performing longitudinal follow-up on these individuals. Over the past two decades under our clinical protocols, we have established a vast bank of clinical data, DNA, RNA and tissue samples enabling us to understand the natural history and genotype/phenotype correlation in Gaucher disease. Our research has shown that although Gaucher disease is classically divided into three types, there is actually a continuum of manifestations, We have uncovered several unexpected phenotypes and have solid evidence that modifiers must contribute to this phenotypic diversity. Studying a family with clinically discordant brothers, we identified our first genetic modifier, the glucocerebrosidase transporter LIMP2. We are now poised to investigate the intricate relationships between clinical phenotypes, metabolic defects and molecular mechanisms in monogenic disorders like Gaucher disease with newly available techniques, including RNAi screens, protein and SNP arrays and whole-exome or genome sequencing. With funding from an NIH Directors award we used RNAi and microRNA screens to explore potential modifiers impacting glucocerebrosidase as well as other lysosomal enzymes, which are providing new research directions. Understanding the mechanisms leading to these diverse phenotypes may help in the identification of modifier genes, and will provide insights relevant to other disorders. To enhance our studies of Gaucher disease and of parkinsonism we have been working to develop new cellular models. We have successfully studied patient derived macrophages in culture and show that they mimic the storage phenotype seen inpatients. We have now also generated induced pluripotent stem cells (iPSCs) from patient fibroblasts and have differentiated these into macrophages and neurons and find that they have an appropriate phenotype with deficient glucocerebrosidase and increased glycolipid storage. iPSC-derived dopaminergic neurons from patients with both Gaucher disease and Parkinson disease demonstrate elevated levels of alpha-synuclein. Another important goal is to develop new treatment strategies for patients. Enzyme replacement therapy for Gaucher disease with imiglucerase has been shown to be clinically effective, but its extremely high cost is of considerable concern both to the public and to health care providers. A potential alternative therapy is the use of small molecules that may function as chemical chaperones that can stabilize and enhance the patient s mutant enzyme. This approach is being explored by studies of the trafficking of glucocerebrosidase and investigations of whether small molecules may enhance the delivery of mutant glucocerebrosidase to the lysosome. In collaboration with NCATS, we have screened large libraries of compounds using mutant forms of the enzyme, which has yielded new leads that are being developed as treatments for Gaucher disease. For the first time, we identified non-inhibitory chaperone molecules that result in translocation of the enzyme to the lysosome and enhancement of activity. These new non-inhibitory leads have been validated in our marcrophage models, and in iPS cells. The therapy resulted in enhanced enzymatic activity, decreased lipid storage and improved cellular function in these models. Treatment of dopaminerigic neurons from patients with parkinsonism also resulted in decreased levels of alpha-synuclein.This approach promises convenient and less costly therapy for Gaucher disease, and may have important implications for the treatment of Parkinson disease.